The Recall-study: Rivastigmine for ECT-induced Cognitive Adverse effects in Late Life Depression: a multicenter, randomized, double-blind, placebo-controlled, crossover trial

Background: Electroconvulsive therapy (ECT) is the most effective treatment for
severe depressions. Unfortunately, several cognitive side effects with a large
pallet of different manifestations and impact often occur. For instance,
postictal agitation ((PIA) with ia motor restlessness and panic like behavior
directly after ECT lasting 5 minutes till one hour), or more mildly general
disorientation recovering within 1-2 hours after ECT and anterograde memory
deficits and retrograde amnesia (both mostly reversible after a few weeks till
several months) are well known. Finally, interictal delirium characterized by
severe confusion which can appear separately form the postictal disorientation
and may take several days to weeks to resolve, mostly in elderly individuals,
has also been described (Selvaraj 2012). In particular the latter may result in
a premature abandoning of ECT, and hence failure to achieve remission of the
depressive disorder.
Considering its beneficial effect on cognition in persons with mild to moderate
Alzheimer*s dementia and the potential beneficial effect on memory deficits in
ECT-treated persons with schizophrenia (Stryjer, 2012) and either major
depressive disorder, bipolar or schizoaffective disorder (Matthews 2013),
treatment with an acetylcholinesterase inhibitor (ie rivastigmine) might be
useful for the prevention or reversion of the interictal delirium as well.

Therefore we designed a randomised double blind placebo controlled crossover
trial embedded in a large cohort-study on ECT-patients, to investigate whether
rivastigmine treatment has a positive effect on the severity and duration of
the interictal delirium. We hypothesize, that rivastigmine addition during ECT
can diminish the interictal delirium, induced by ECT.

Main objectives: The main aim of this study is twofold. We aim to (1)
investigate whether rivastigmine can be used as a novel treatment to reduce
ECT-induced interictal delirium and (2) to gain further insight into
differences in determinants between inter-ictal delirium and adjacent cognitive
disturbances induced by ECT, including post-ictal agitation and mild general
disorientation of short duration. The main research questions are as follows:
1. Can rivastigmine 4.6 mg AN diminish the severity of ECT induced interictal
delirium?
2. What are the predictors of interictal delirium among depressed persons
during ECT?
3. What are the predictors of rivastigmine treatment response?
4. Does rivastigmine affect ECT parameters such as bloodpressure, heart rate
and seizure threshold and time of - anesthesia induced - muscle relaxation?
5. What is the tolerability of rivastigmine during ECT? Which side-effects
occur?
6. Do determinants of inter-ictal delirium and adjacent cognitive disturbances
induced by ECT, including post-ictal agitation and mild general disorientation
of short duration, differ?
7. What is the Cost Effectiveness of rivastigmine during ECT?

It is a double blind randomised placebo controlled crossover study, embedded
in a large cohort study on ECT patients.

Eligible patients or their proxies will be verbally informed by their doctor on
the content of the study, benefits and risks, and will receive a patient
information folder on the nature of the study (version number, see appendix).
The time to consider participation to the trial will be 24 hours maximum.
Subsequently the patient or their proxy is asked for informed consent for
separately:
- participation to the large cohort
- participation to the trial

After obtaining written informed consent, the patient will be included in the
large cohort and will receive treament according to standard care. Extra
researchdata will be obtained (see burden and risk section)
ECT will take place twice a week.
One day after ECT the patient will be

One day after ECT the patient will be assessed on the presence of the
interictal delirium by
1. Meeting the criteria of a delirium by the Confusion Assessment Method (CAM).
For a diagnosis of delirium by CAM, the patient must display: 1) Presence of
acute onset and fluctuating discourse, and 2) Inattention, and either 3)
Disorganized thinking or 4) Altered level of consciousnes
2. Decline of the Mini Mental State Examination (MMSE) of at least 4 points

When a patient fulfils the inclusion criteria for the trial, a transdermal
rivastigmine patch (group A) or placebo patch (group B) will be applicated the
evening before ECT treatment and will be removed 24hrs after application. After
two ECT sessions, group A will receive placebo treatment for two sessions and
group B will receive a rivastigmine patch for two sessions.

Both study arms will receive standard hospital care troughout the trial.

Each patient who signed informed consent and meets the criteria for interictal
delirium will be randomized to one of both treatment arms (A or B).
In arm A a rivastgmine patch will be applicated during two consecutive ECT
sessions for 24 hrs (application the evening before ECT and removal after 24
hrs). The next two consecutive ECT sessions, the patient will receive a placebo
patch.
In B, the patient will receive the patches in opposite order: the first two
sessions a placebo patch for 24 hrs and the two consecutive sessions a
rivastgmine patch.

The dosis if the rivastigminepatch is the minimum dose and individuals are only
exposed 2 times during 24 hrs to the drug. Side effects will be closely
monitored
There will one extra venipuncture and collection of two urine morning samples
for the cohort. Many examinations are part of standard care. Additions to
common clinical practice are: Apathy-scale, IPAQ, 2 times Short Physical
Performance Battery (SPPB, including 3 timed performance tests: walking speed,
Tandem stand for balance and chair stand test) 2 times handgrip strength and
EEG, all non-invasive methods.
After each ECT session several cognitive tests and a side effects questionnary
(see section primary and secondary outcomes) and till 90 minutes after ECT
maximum reorientation time will be assessed both in the cohort as during the
trial. Side essects questionnary will be held for six times.